title: c-Abl-dependent molecular circuitry involving Smad5 and phosphatidylinositol 3-kinase regulates bone morphogenetic protein-2-induced osteogenesis.
abstract: Skeletal remodeling consists of timely formation and resorption of bone by osteoblasts and osteoclasts in a quantitative manner. Patients with chronic myeloid leukemia receiving inhibitors of c-Abl tyrosine kinase often show reduced bone remodeling due to impaired osteoblast and osteoclast function. BMP-2 plays a significant role in bone generation and resorption by contributing to the formation of mature osteoblasts and osteoclasts. The effects of c-Abl on BMP-2-induced bone remodeling and the underlying mechanisms are not well studied. Using a pharmacological inhibitor and expression of a dominant negative mutant of c-Abl, we show an essential role of this tyrosine kinase in the development of bone nodules containing mature osteoblasts and formation of multinucleated osteoclasts in response to BMP-2. Calvarial osteoblasts prepared from c-Abl null mice showed the absolute requirement of this tyrosine kinase in maturation of osteoblasts and osteoclasts. Activation of phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signaling by BMP-2 leads to osteoblast differentiation. Remarkably, inhibition of c-Abl significantly suppressed BMP-2-stimulated PI 3-kinase activity and its downstream Akt phosphorylation. Interestingly, c-Abl regulated BMP-2-induced osteoclastogenic CSF-1 expression. More importantly, we identified the requirements of c-Abl in BMP-2 autoregulation and the expressions of alkaline phosphatase and osterix that are necessary for osteoblast differentiation. c-Abl contributed to BMP receptor-specific Smad-dependent transcription of CSF-1, osterix, and BMP-2. Finally, c-Abl associates with BMP receptor IA and regulates phosphorylation of Smad in response to BMP-2. We propose that activation of c-Abl is an important step, which induces into two signaling pathways involving noncanonical PI 3-kinase and canonical Smads to integrate BMP-2-induced osteogenesis.
authors.affiliation: Veterans Affairs Research, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA. choudhury@uthscsa.edu
authors.forename: Nandini
authors.initials: N
authors.lastname: Ghosh-Choudhury
authors.forename: Chandi C
authors.initials: CC
authors.lastname: Mandal
authors.forename: Falguni
authors.initials: F
authors.lastname: Das
authors.forename: Suthakar
authors.initials: S
authors.lastname: Ganapathy
authors.forename: Seema
authors.initials: S
authors.lastname: Ahuja
authors.forename: Goutam
authors.initials: G
authors.lastname: Ghosh Choudhury
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012886:Skull / Q000166:cytology / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D016315:Proto-Oncogene Proteins c-abl; D051057:Proto-Oncogene Proteins c-akt; D000469:Alkaline Phosphatase
keywords: Bone Morphogenetic Protein (BMP); Colony-stimulating Factor-1 (CSF-1); Osteoblasts; Osteoclast; PI 3-Kinase; SMAD Transcription Factor; c-Abl